CN117486787A - Preparation method of apixaban intermediate - Google Patents
Preparation method of apixaban intermediate Download PDFInfo
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- CN117486787A CN117486787A CN202311442055.3A CN202311442055A CN117486787A CN 117486787 A CN117486787 A CN 117486787A CN 202311442055 A CN202311442055 A CN 202311442055A CN 117486787 A CN117486787 A CN 117486787A
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- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229960003886 apixaban Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 66
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000003054 catalyst Substances 0.000 claims abstract description 29
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 22
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000003960 organic solvent Substances 0.000 claims abstract description 19
- 239000007800 oxidant agent Substances 0.000 claims abstract description 19
- 230000001590 oxidative effect Effects 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 239000012024 dehydrating agents Substances 0.000 claims abstract description 13
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- CZGCEKJOLUNIFY-UHFFFAOYSA-N 4-Chloronitrobenzene Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1 CZGCEKJOLUNIFY-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 40
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000292 calcium oxide Substances 0.000 claims description 3
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 28
- 239000002994 raw material Substances 0.000 abstract description 8
- 230000008901 benefit Effects 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- 239000012074 organic phase Substances 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000001704 evaporation Methods 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 230000008030 elimination Effects 0.000 description 6
- 238000003379 elimination reaction Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000007363 ring formation reaction Methods 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000012047 saturated solution Substances 0.000 description 5
- 235000010265 sodium sulphite Nutrition 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 239000008096 xylene Substances 0.000 description 5
- 150000003954 δ-lactams Chemical group 0.000 description 5
- 230000009435 amidation Effects 0.000 description 4
- 238000007112 amidation reaction Methods 0.000 description 4
- VLVCDUSVTXIWGW-UHFFFAOYSA-N 4-iodoaniline Chemical compound NC1=CC=C(I)C=C1 VLVCDUSVTXIWGW-UHFFFAOYSA-N 0.000 description 3
- OKRUMSWHDWKGHA-UHFFFAOYSA-N 5-bromopentanoyl chloride Chemical compound ClC(=O)CCCCBr OKRUMSWHDWKGHA-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- XUWHAWMETYGRKB-UHFFFAOYSA-N delta-valerolactam Natural products O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 206010014522 Embolism venous Diseases 0.000 description 2
- 238000006887 Ullmann reaction Methods 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000004043 venous thromboembolism Diseases 0.000 description 2
- SKWFBUABBUHYTM-UHFFFAOYSA-N 1-(4-iodophenyl)piperidine-2,3-dione Chemical compound C1=CC(I)=CC=C1N1C(=O)C(=O)CCC1 SKWFBUABBUHYTM-UHFFFAOYSA-N 0.000 description 1
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 description 1
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 229940123688 Direct Factor Xa inhibitor Drugs 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000011882 arthroplasty Methods 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 229940047562 eliquis Drugs 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000003127 knee Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical class CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of apixaban intermediate, which is characterized by comprising the following steps: dissolving a compound I in an organic solvent, adding a catalyst into p-chloronitrobenzene, and stirring at room temperature for reaction for 6-8 hours to obtain a compound II; dissolving a compound II in an organic solvent, adding an oxidant, adding a catalyst, heating at 35-40 ℃ for reaction, and obtaining a compound III after the reaction is finished; thirdly, dissolving the compound III in an organic solvent, adding a dehydrating agent, adding morpholine, reacting for 6-8 hours at 35-40 ℃, and separating a product after the reaction is finished to obtain the compound IV. The beneficial effects of the invention are as follows: the method has the advantages of easily available raw materials, low cost, short reaction route, simple operation, high yield, fewer byproducts of the product, easy separation of the product and good reaction selectivity, and is suitable for the requirements of industrial production.
Description
Technical Field
The invention relates to the technical field related to synthesis of medical intermediates, in particular to a preparation method of apixaban intermediates.
Background
Apixaban (Apixaban, i), chemical name l- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide, a novel direct factor Xa inhibitor developed by the combination of bai-time meishi precious company and the fei company, was approved by the european union in month 2011, approved by the FDA in the united states in month 12, 28, marketed under the trade name Eliquis, for the prevention of Venous Thromboembolism (VTE) and atrial fibrillation in adult patients with hip or knee arthroplasty.
U.S. patent No. 8884016 proposes a technical route for the synthesis of apixaban via 1- (4-iodophenyl) piperidine-2, 3-dione, the reaction route being as follows:
route one
World patent W02003049681 disclosed in 2003 by Bristol-Myers Squibb company takes p-iodoaniline and 5-bromopentanoyl chloride as starting materials, and the target compound apixaban is obtained by amidation, cyclization, alpha-position dichlorination of amide, condensation elimination, cyclization elimination and Ullmann coupling; the synthetic route is as follows:
route two
The disadvantage of this route is that: the price of the initial raw materials (p-iodoaniline and 5-bromovaleryl chloride) is higher, thus increasing the production cost; the Ullmann coupling reaction needs high-temperature high-pressure reaction and has harsh conditions; the overall yield of this route was only 1.3%.
In order to overcome the defects of the synthetic route, the China patent CN101967145 published in 2011 of China university of Tongshi adopts paranitroaniline as a starting material, and the target compound apixaban intermediate is obtained through amidation cyclization, dichlorination, elimination, cyclization elimination, catalytic hydrogenation reduction and amidation cyclization in sequence; the synthetic route is as follows:
route three
The synthetic yield of the route is high, the total yield is 35%, the raw materials are easy to obtain, and the cost is low.
In all of the above routes it is necessary to construct the delta-lactam structure first,then introducing double bond and substituent at ortho position of carbonyl group of delta-cyclic lactam, the present route adopts multi-carbonyl cyclic amide compound as initial raw material, and 1- (4-iodophenyl) piperidine-2, 3-diketone is used as one of key intermediates in the synthetic route, and the prior art is characterized by that the compound is prepared byIs prepared by decarboxylation and hydrolysis to remove the group Z (carboxyl, ester or cyano). This method is mentioned only in US8884016 and there is no specific solution.
The raw materials are not easy to obtain, the compound containing the multi-carbonyl and having the Z (carboxyl, ester or cyano) group is not easy to synthesize, the similar structure can be finished by a coupling reaction catalyzed by noble metal, the cost is high, and the method is not suitable for mass production and preparation.
The second and third routes introduce double bond and substituent at the ortho position of carbonyl of delta-lactam through chlorination and elimination of multi-step reaction, so that further reaction is performed, the ortho position of carbonyl of delta-lactam in the route introduces double bond and substituent to be a key step in synthesis, the price of the initial raw materials (p-iodoaniline and 5-bromovaleryl chloride) in the second route is higher, the raw materials in the third route are easy to obtain, the cost is low, but sodium hydride is used as a condensing agent in the amidation cyclization step, the production cost is higher, and the operation danger is high; the 5-halogenated valeryl chloride is a genotoxic impurity, the yield and purity of the product are affected, and the yields of double bonds and substituents introduced at the ortho positions of carbonyl groups of delta-cyclic lactam through chlorination and elimination are low in both the second and third routes, so that the yield of subsequent reactions is reduced, the overall reaction yield is affected, and the production cost is increased.
Disclosure of Invention
Aiming at the defects of the method for constructing a delta-lactam structure and then introducing double bonds and substituents at the ortho position of a carbonyl group of the delta-lactam in each reaction route, the olefin is directly formed by oxidation, and the reaction route is as follows:
the invention adopts the following technical scheme: 1. the preparation method of the apixaban intermediate is characterized by comprising the following steps of:
a method for preparing apixaban intermediate, comprising the following steps:
firstly, dissolving a compound I in an organic solvent, adding p-chloronitrobenzene, adding a catalyst, stirring at room temperature for reaction for 6-8 hours, and separating a product after the reaction is finished to obtain a compound II;
secondly, dissolving the compound II obtained in the first step in an organic solvent, adding an oxidant, adding a catalyst, heating at 35-40 ℃ for reaction, and separating a product after the reaction is finished to obtain a compound III;
and thirdly, dissolving the compound III obtained in the second step in an organic solvent, adding morpholine, adding a dehydrating agent, reacting for 6-8 hours at 35-40 ℃, and separating a product after the reaction is finished to obtain a compound IV.
Further, the first-step reaction solvent is one of xylene and chloroform.
Further, the second-step reaction solvent is one of dimethyl sulfoxide (DMSO) or chloroform.
Further, the solvent used in the third reaction step is one of dimethyl sulfoxide (DMSO) and Dichloromethane (DCM).
Further, the catalyst in the first-step reaction system is sodium hydroxide or potassium hydroxide.
Further, in the second step of reaction, the oxidant is 2-iodoxybenzoic acid, and the catalyst is CeCl 3.· 7H 2 O。
Furthermore, the dehydrating agent used in the third step is one of potassium carbonate or calcium oxide, and the dosage of the dehydrating agent is 2-3 times of the molar quantity of the compound III.
Further, the dosage of the catalyst in the first step is 3-5 times of the molar weight of the compound I, and the molar ratio of the dosage of the p-chloronitrobenzene to the compound I is 1:1.
Further, the amount of the oxidizing agent used in the second reaction is 2.5 to 3.5 times the molar amount of the compound II, preferably 1:3.0, and the amount of the catalyst used is 10 to 20mol%, preferably 15mol%, of the compound II.
10. The method for preparing apixaban intermediate according to claim 1, wherein: the molar ratio of morpholine to compound III used in the third reaction step is 1:1.0 to 1.5, preferably 1:1.2.
The beneficial effects of the invention are as follows:
1. the material of the invention is easy to obtain, the reactant I has a plurality of synthetic routes, other substances can be easily obtained through market purchase, so that various reactants are easy to obtain, the production cost is lower, the production cost can be saved from the aspect of raw materials, and the economic benefit is effectively increased;
2. the method has the advantages that the yield of the product is high, the activity of amino reaction can be increased by the alkenyl in the first step of reaction, so that the product has higher yield, the oxidation reaction in the second step has strong oxidation capability on the alkenyl, and the third step has higher selectivity and reaction activity, so that the reaction in each step of the route has higher reaction selectivity and yield, the byproducts are fewer, the produced product is easy to separate, and the product with higher purity can be obtained in high yield;
3. the method has the advantages of simple route operation, uncomplicated process route, small pollution of reactants and products, simple post-treatment, and suitability for industrialized large-scale production, and meets the concept of green chemistry.
Drawings
FIG. 1 is a schematic illustration of a process flow diagram of a comparative example synthetic route of the present invention;
FIG. 2 is a schematic diagram of a comparative example synthetic route II process flow of the present invention;
FIG. 3 is a schematic diagram of a three-process scheme of a comparative example synthetic route of the present invention;
FIG. 4 is a schematic illustration of the synthetic route process flow of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the embodiments of the present invention and the accompanying drawings, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Dissolving 0.1mol (8.3 g) of compound I in 200ml of organic solvent xylene under the protection of nitrogen, adding 0.1mol of p-chloronitrobenzene, adding 0.3mol of sodium hydroxide serving as a catalyst alkali reagent, stirring at room temperature for reaction for 6-8 hours, slowly dripping dilute hydrochloric acid to adjust the pH of the solution to be neutral after the reaction is finished, separating an organic phase, extracting an aqueous phase for 2-3 times by using 80ml of xylene, merging the organic phase, adding 100ml of saturated saline water into the organic phase for washing for 2-3 times, evaporating and crystallizing under reduced pressure, dissolving a product by using 40ml of petroleum ether, filtering, evaporating and crystallizing to obtain 19.5g of compound II, wherein the yield is 95.6% and the purity is 95.9%;
in a second step, 0.1mol (20.4 g) of the compound II obtained in the first step is dissolved in 200ml of dimethyl sulfoxide (DMSO), 0.3mol of 2-iodoxybenzoic acid (IBX) as an oxidant is added, and 0.015mol of CeCl as a catalyst is added under the protection of nitrogen 3.· 7H 2 O, heating at 35-40 ℃ for reaction for 6-8 h, adding sodium sulfite saturated solution to neutralize oxidant after the reaction is finished, adding saturated sodium bicarbonate solution to neutralize to neutrality, extracting the product in the solution with 80ml of dichloromethane for 2-3 times, separating an organic phase, washing the organic phase with saturated saline water for 2-3 times, evaporating and crystallizing to obtain 21.6g of compound III, wherein the yield is 92.3% and the purity is 94.8%;
thirdly, 0.1mol (23.4 g) of the compound III obtained in the second step is dissolved in 200ml of organic solvent methylene dichloride under the protection of nitrogen, 0.2mol of catalyst dehydrating agent potassium carbonate is added, 0.12mol of morpholine is gradually added dropwise, after the dropwise addition is finished, the reaction is carried out for 6 to 8 hours at the temperature of 35 to 40 ℃, dilute hydrochloric acid is added to remove redundant morpholine after the reaction is finished, an organic phase is separated, the organic phase is washed for 2 to 3 times by adding saturated sodium chloride solution, evaporation crystallization is carried out, and the product is recrystallized by 80ml of toluene, thus 28.6g of compound IV is obtained, the yield is 94.3%, and the purity is 96.9%.
Example 2
Dissolving 0.1mol (8.3 g) of compound I in 200ml of organic solvent chloroform under the protection of nitrogen, adding 0.1mol of p-chloronitrobenzene, adding 0.3mol of sodium hydroxide serving as a catalyst alkali reagent, stirring at room temperature for reaction for 6-8 hours, slowly dripping dilute hydrochloric acid to adjust the pH of a solution to be neutral after the reaction is finished, separating an organic phase, extracting an aqueous phase with 80ml of dimethylbenzene for 2-3 times, merging the organic phase, adding 100ml of saturated saline water into the organic phase for washing for 2-3 times, evaporating and crystallizing under reduced pressure, dissolving a product with 40ml of petroleum ether, filtering, evaporating and crystallizing to obtain 19.4g of compound II, wherein the yield is 95.1% and the purity is 95.6%;
example 3
Dissolving 0.1mol (8.3 g) of compound I in 200ml of organic solvent xylene under the protection of nitrogen, adding 0.1mol of p-chloronitrobenzene, adding 0.5mol of sodium hydroxide serving as a catalyst alkali reagent, stirring at room temperature for reaction for 6-8 hours, slowly dripping dilute hydrochloric acid to adjust the pH of the solution to be neutral after the reaction is finished, separating an organic phase, extracting an aqueous phase with 80ml of xylene for 2-3 times, merging the organic phase, adding 100ml of saturated saline water into the organic phase for washing for 2-3 times, evaporating and crystallizing under reduced pressure, dissolving a product with 40ml of petroleum ether, filtering, evaporating and crystallizing to obtain 19.0g of compound II, wherein the yield is 93.2% and the purity is 95.3%;
example 4
In the second step, 0.1mol (20.4 g) of the compound II obtained in the first step is dissolved in 200ml of chloroform as an organic solvent under the protection of nitrogen, 0.3mol of 2-iodoxybenzoic acid (IBX) as an oxidant is added, and 0.015mol of CeCl as a catalyst is added 3.· 7H 2 O, heating at 35-40 ℃ for reaction for 6-8 h, adding sodium sulfite saturated solution to neutralize oxidant after the reaction is finished, adding saturated sodium bicarbonate solution to neutralize to neutrality, separating an organic phase, washing the organic phase with saturated saline water for 2-3 times, evaporating and crystallizing to obtain 21.5g of compound III, wherein the yield is 91.9%, and the purity is 94.7%;
example 5
In the second step, 0.1mol (20.4 g) of the compound II obtained in the first step is dissolved in 200ml of dimethyl sulfoxide (DMSO), 0.35mol of 2-iodoxybenzoic acid (IBX) as an oxidant is added, and 0.015mol of CeCl as a catalyst is added under the protection of nitrogen 3.· 7H 2 O, heating and reacting for 6-8 h at 35-40 ℃, and adding sulfurous acid after the reaction is finishedNeutralizing oxidant in saturated sodium solution, adding saturated sodium bicarbonate solution to neutralize, extracting the product in the solution with 80ml dichloromethane for 2-3 times, separating organic phase, washing the organic phase with saturated saline water for 2-3 times, evaporating and crystallizing to obtain 21.6g of compound III, yield 92.3% and purity 94.9%;
example 6
In a second step, 0.1mol (20.4 g) of the compound II obtained in the first step is dissolved in 200ml of dimethyl sulfoxide (DMSO), 0.25mol of 2-iodoxybenzoic acid (IBX) as an oxidant is added, and 0.015mol of CeCl as a catalyst is added under the protection of nitrogen 3.· 7H 2 O, heating at 35-40 ℃ for reaction for 6-8 h, adding sodium sulfite saturated solution to neutralize oxidant after the reaction is finished, adding saturated sodium bicarbonate solution to neutralize to neutrality, extracting the product in the solution with 80ml of dichloromethane for 2-3 times, separating an organic phase, washing the organic phase with saturated saline water for 2-3 times, evaporating and crystallizing to obtain 21.2g of compound III, wherein the yield is 90.6% and the purity is 95.1%;
example 7
In the second step, 0.1mol (20.4 g) of the compound II obtained in the first step is dissolved in 200ml of dimethyl sulfoxide (DMSO), 0.3mol of 2-iodoxybenzoic acid (IBX) as an oxidant is added, and 0.010mol of CeCl as a catalyst is added under the protection of nitrogen 3.· 7H 2 O, heating at 35-40 ℃ for reaction for 6-8 h, adding sodium sulfite saturated solution to neutralize oxidant after the reaction is finished, adding saturated sodium bicarbonate solution to neutralize to neutrality, extracting the product in the solution with 80ml of dichloromethane for 2-3 times, separating an organic phase, washing the organic phase with saturated saline water for 2-3 times, evaporating and crystallizing to obtain 21.0g of compound III, wherein the yield is 89.7% and the purity is 94.8%;
example 8
In a second step, 0.1mol (20.4 g) of the compound II obtained in the first step is dissolved in 200ml of dimethyl sulfoxide (DMSO), 0.3mol of 2-iodoxybenzoic acid (IBX) as an oxidant is added, and 0.02mol of CeCl as a catalyst is added under the protection of nitrogen 3.· 7H 2 O, heating at 35-40 ℃ for reaction for 6-8 h, adding sodium sulfite saturated solution to neutralize oxidant after reaction, adding saturated sodium bicarbonate solution to neutralize to neutrality, and obtaining the product in the solutionExtracting with 80ml dichloromethane for 2-3 times, separating organic phase, washing the organic phase with saturated saline water for 2-3 times, evaporating and crystallizing to obtain 21.6g compound III, yield 92.7%, purity 95.2%;
example 9
Thirdly, 0.1mol (23.4 g) of the compound III obtained in the second reaction step is dissolved in 200ml of organic solvent dimethyl sulfoxide under the protection of nitrogen, 0.2mol of catalyst dehydrating agent potassium carbonate is added, 0.12mol of morpholine is gradually added dropwise, after the dropwise addition is finished, the reaction is carried out for 6 to 8 hours at the temperature of 35 to 40 ℃, dilute hydrochloric acid is added to remove redundant morpholine after the reaction is finished, the product in the solution is extracted for 2 to 3 times by 80ml of dichloromethane, an organic phase is separated, the organic phase is washed for 2 to 3 times by adding saturated sodium chloride solution, the product is evaporated and crystallized, and the product is recrystallized by 80ml of toluene to obtain 28.2g of compound IV, the yield is 94.3%, and the purity is 96.9%.
Example 10
Thirdly, 0.1mol (23.4 g) of the compound III obtained in the second step is dissolved in 200ml of organic solvent methylene dichloride under the protection of nitrogen, 0.2mol of catalyst dehydrating agent calcium oxide is added, 0.12mol of morpholine is gradually added dropwise, after the dropwise addition is finished, the reaction is carried out for 6 to 8 hours at the temperature of 35 to 40 ℃, dilute hydrochloric acid is added to remove redundant morpholine after the reaction is finished, an organic phase is separated, the organic phase is washed for 2 to 3 times by adding saturated sodium chloride solution, evaporation crystallization is carried out, and the product is recrystallized by 80ml of toluene, thus 28.0g of compound IV is obtained, the yield is 92.3%, and the purity is 96.5%.
Example 11
Thirdly, 0.1mol (23.4 g) of the compound III obtained in the second step is dissolved in 200ml of organic solvent methylene dichloride under the protection of nitrogen, 0.3mol of catalyst dehydrating agent potassium carbonate is added, 0.12mol of morpholine is gradually added dropwise, after the dropwise addition is finished, the reaction is carried out for 6 to 8 hours at the temperature of 35 to 40 ℃, dilute hydrochloric acid is added to remove redundant morpholine after the reaction is finished, an organic phase is separated, the organic phase is washed for 2 to 3 times by adding saturated sodium chloride solution, evaporation crystallization is carried out, and the product is recrystallized by 80ml of toluene, thus 28.4g of compound IV is obtained, the yield is 93.7%, and the purity is 96.6%.
Example 12
Thirdly, 0.1mol (23.4 g) of the compound III obtained in the second step is dissolved in 200ml of organic solvent methylene dichloride under the protection of nitrogen, 0.2mol of catalyst dehydrating agent potassium carbonate is added, 0.10mol of morpholine is gradually added dropwise, after the dropwise addition is finished, the reaction is carried out for 6 to 8 hours at the temperature of 35 to 40 ℃, dilute hydrochloric acid is added to remove redundant morpholine after the reaction is finished, an organic phase is separated, the organic phase is washed for 2 to 3 times by adding saturated sodium chloride solution, evaporation crystallization is carried out, and the product is recrystallized by 80ml of toluene, thus 28.3g of compound IV is obtained, the yield is 93.4%, and the purity is 96.7%.
Example 13
Thirdly, 0.1mol (23.4 g) of the compound III obtained in the second step is dissolved in 200ml of organic solvent methylene dichloride under the protection of nitrogen, 0.2mol of catalyst dehydrating agent potassium carbonate is added, 0.15mol of morpholine is gradually added dropwise, after the dropwise addition is finished, the reaction is carried out for 6 to 8 hours at the temperature of 35 to 40 ℃, dilute hydrochloric acid is added to remove redundant morpholine after the reaction is finished, an organic phase is separated, the organic phase is washed for 2 to 3 times by adding saturated sodium chloride solution, evaporation crystallization is carried out, and the product is recrystallized by 80ml of toluene, thus 28.7g of compound IV is obtained, the yield is 94.7%, and the purity is 97.0%.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.
Claims (10)
1. The preparation method of the apixaban intermediate is characterized by comprising the following steps of:
firstly, dissolving a compound I in an organic solvent, adding p-chloronitrobenzene, adding a catalyst, stirring at room temperature for reaction for 6-8 hours, and separating a product after the reaction is finished to obtain a compound II;
secondly, dissolving the compound II obtained in the first step in an organic solvent, adding an oxidant, adding a catalyst, heating at 35-40 ℃ for reaction, and separating a product after the reaction is finished to obtain a compound III;
and thirdly, dissolving the compound III obtained in the second step in an organic solvent, adding morpholine, adding a dehydrating agent, reacting for 6-8 hours at 35-40 ℃, and separating a product after the reaction is finished to obtain a compound IV.
2. The method for preparing apixaban intermediate according to claim 1, wherein: the first-step reaction solvent is one of dimethylbenzene and chloroform.
3. The method for preparing apixaban intermediate according to claim 1, wherein: the second step reaction solvent is one of dimethyl sulfoxide (DMSO) or chloroform.
4. The method for preparing apixaban intermediate according to claim 1, wherein: the solvent used in the third reaction step is one of dimethyl sulfoxide (DMSO) and Dichloromethane (DCM).
5. The method for preparing apixaban intermediate according to claim 1, wherein: the catalyst in the first-step reaction system is sodium hydroxide or potassium hydroxide.
6. The method for preparing apixaban intermediate according to claim 1, wherein: the oxidant in the second step is 2-iodoxybenzoic acid, and the catalyst is CeCl 3.· 7H 2 O。
7. The method for preparing apixaban intermediate according to claim 1, wherein: the dehydrating agent used in the third step is one of potassium carbonate or calcium oxide, and the dosage of the dehydrating agent is 2-3 times of the molar quantity of the compound III.
8. The method for preparing apixaban intermediate according to claim 1, wherein: the dosage of the catalyst in the first step is 3-5 times of the molar weight of the compound I, and the molar ratio of the dosage of the p-chloronitrobenzene to the compound I is 1:1.
9. The method for preparing apixaban intermediate according to claim 1, wherein: the dosage of the oxidant in the second step is 2.5-3.5 times of the molar weight of the compound II, and the dosage of the catalyst is 10-20 mol% of the compound II.
10. The method for preparing apixaban intermediate according to claim 1, wherein: the molar ratio of the morpholine to the compound III used in the third reaction step is 1:1.0-1.5.
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